Malignant glioma, the most common primary brain tumor subtype, is aggressive and neurologically destructive. The mean survival duration of patients with glioblastoma multiforme (GBM), the most common form of glioma, is approximately 1 year and there is no effective therapy to date. Little is known about the molecular mechanisms underlying GBM oncogenesis. The malignant phenotype of human GBM may be driven by GBM-derived stem-like cells (GSCs). One of the key issues for our understanding of cancer stem cells is to define the molecular circuitry that drives the development and self-renewal of the cancer stem cells. Based on our recent experimental results, we propose to evaluate the novel hypothesis that FoxM1, which is abnormally expressed in human GBM-derived stem-like cells (GSCs), causes a high self-renewal rate in the "stem-like" cells present in the tumor, possibly through a PDGF-A-mediated mechanism, and, thus contribute to tumorigenicity. Here, we propose to evaluate the oncogenic function of FoxM1 in cooperation with p53 tumor suppressor gene in oncogenesis of neural stem cells;and the essential role of FoxM1 in maintaining the characteristics of glioma stem-like cells. If the Specific Aims of this grant application are completed, not only will we understand a new mechanism of GBM molecular oncogenesis through abnormal maintenance of GBM-derived cancer "stem" cell self-renewal via FoxM1 expression, but also will we learn whether FoxM1 can serve as potential therapeutic targets. This information will have potentially high translational impact. In the long term, our study may lead to the validation of molecular targets that can be used in designing effective strategies to control this deadly disease in clinics. PUBLIC HEALTH RELEVANCE: The mean survival duration of patients with glioblastoma multiforme (GBM), the most common form of glioma, is approximately 1 year and there is no effective therapy to date. If the Specific Aims of this grant application are completed, not only will we understand a new mechanism of GBM tumorigenesis through abnormal maintenance of GBM-derived cancer "stem" cell self-renewal via FoxM1, but we will also learn whether FoxM1 or its target PDGF-A can function as potential therapeutic targets. This information will have potential translational impact. In the long term, our study may lead to the identification of molecular targets that can be used in designing effective strategies to control this deadly disease.